A range of intracellular as well as extracellular signals are known to target the cell division cycle and apoptosis pathways and function to maintain homeostasis in normal tissues. The pathways regulating the cell division cycle as well as apoptosis are frequently altered in inflammation-associated disorders such as cancers. The regulators of mitotic control and/or apoptosis signaling therefore remain important targets for current and future intervention strategies for such disorders.
The identification and characterization of a peri-nuclear protein termed CARP-1/CCAR1 that functions to regulate chemotherapy-dependent apoptosis signaling has been reported. Depletion of CARP-1 confers resistance to apoptosis induced by chemotherapeutic agents such as adriamycin or Iressa. CARP-1 functions in a biphasic manner as a co-activator of signaling by steroid receptors and tumor suppressor p53. CARP-1 expression enhances CDKI p21WAF1CIP1 levels and apoptosis while attenuating expression of mediators of cell-cycle and/or proliferation such as c-Myc, cyclin B, topoisomerase IIα, p21Rac1, and mitogen-activated protein kinase (MAPK)/extracellular signal regulating kinase (ERK) 1/2 regulator MEK2. CARP-1 is a serine and tyrosine phospho-protein that possesses multiple, non-overlapping apoptosis-inducing subdomains. CARP-1 tyrosine192 regulates apoptosis signaling by EGFRs, while CARP-1-dependent apoptosis involves activation of stress-activated protein kinase (SAPK) p38α/β, and caspase-9.
The APC/C is a multiprotein complex with E3 ubiquitin ligase activity. APC/C is inhibited by activation of the mitotic spindle checkpoint during the cell division cycle. APC/C-targeting/activating molecules such as securin, polo-like kinase, aurora kinase, and SnoN are potential oncogenes that often promote dysregulation of APC/C. APC/C is composed of at least 12 subunits, which contains tetratricopeptide repeat proteins (APC-3, 5, 6, 7, and 8), a cullin homology protein (APC-2), and a ring-H2 finger domain protein (APC-11). APC/C requires two WD40 repeat-containing coactivators, Cdc20 and Cdh1, to recruit and select various substrates at different stages of the cell cycle. APC/CCdc20 promotes metaphase/anaphase transition by ubiquitinating and degrading securin, an inhibitor of separase that participates in degradation of the chromatin cohesion complex. APC/CCdc20 also ubiquitinates cyclin-B1 and accelerates its loss during late mitosis to promote exit from M phase. In addition, APC/C targets various cell cycle regulatory molecules, including spindle-associated proteins, DNA replication inhibitors, and mitotic kinases. Alterations in APC/C complex proteins have been noted in breast and colon cancer cells as well as primary colon cancers, while endogenous as well as synthetic inhibitors targeting APC/C-activating oncogenes or the APC/C complex have also been recently described. A yeast-two-hybrid (Y2H) screen has revealed CARP-1 interaction with the APC-2 protein. Antagonists of CARP-1 binding with APC-2 were identified (e.g. CFMs, CARP-1 Functional Mimetics).
Accordingly, there is a need for additional agents that treat cancer including agents that treat cancer via novel mechanisms of action. There is also a need for agents that treat breast cancer including drug resistant breast cancers.